Tiotropium bromide is known from European Patent Application EP 418 716 A1 and has the following chemical structure:
Tiotropium bromide is a highly effective anticholinergic with a long-lasting effect, which may be used to treat respiratory complaints, particularly COPD (chronic obstructive pulmonary disease) and asthma. By tiotropium is meant the free ammonium cation.
Tiotropium bromide is preferably administered by inhalation. Suitable inhalable powders packed into appropriate capsules (inhalettes) may be used. Alternatively, it may be administered by the use of suitable inhalable aerosols. These also include powdered inhalable aerosols which contain, for example, HFA134a, HFA227 or mixtures thereof as propellent gas.
The correct manufacture of the abovementioned compositions which are suitable for use for the administration of a pharmaceutically active substance by inhalation is based on various parameters which are connected with the nature of the active substance itself. In pharmaceutical compositions which are used like tiotropium bromide in the form of inhalable powders or inhalable aerosols, the crystalline active substance is used in ground (micronised) form for preparing the formulation. Since the pharmaceutical quality of a pharmaceutical formulation requires that the active substance should always have the same crystalline modification, the stability and properties of the crystalline active substance are subject to stringent requirements from this point of view as well. It is particularly desirable that the active substance should be prepared in the form of a uniform and clearly defined crystalline modification. It is also particularly desirable that the active substance be prepared in a crystalline form which is characterised by a high degree of stability even over long storage periods. The lower the tendency of a crystalline modification to absorb moisture, for example, the greater the physical stability of its crystal structure.
The aim of the invention is therefore to provide a new stable crystal form of the compound tiotropium bromide which meets the high demands mentioned above that are made of any pharmaceutically active substance. The present invention sets out in particular to provide a crystalline modification of tiotropium bromide which has only limited hygroscopic characteristics.